The role of mitochondrial apoptotic pathway in islet amyloid-induced β-cell death

Mol Cell Endocrinol. 2021 Nov 1;537:111424. doi: 10.1016/j.mce.2021.111424. Epub 2021 Aug 14.

Abstract

Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to β-cell death in type 2 diabetes. We previously showed that extracellular hIAPP aggregates promote Fas-mediated β-cell apoptosis. Here, we tested if hIAPP aggregates can trigger the mitochondrial apoptotic pathway (MAP). hIAPP aggregation in Ad-hIAPP transduced INS-1 and human islet β-cells promoted cytochrome c release, caspase-9 activation and apoptosis, which were reduced by Bax inhibitor. Amyloid formation in hIAPP-expressing mouse islets during culture increased caspase-9 activation in β-cells. Ad-hIAPP transduced islets from CytcKA/KA and BaxBak βDKO mice (models of blocked MAP), had lower caspase-9-positive and apoptotic β-cells than transduced wild-type islets, despite comparable amyloid formation. Blocking Fas (markedly) and Bax or caspase-9 (modestly) reduced β-cell death induced by extracellular hIAPP aggregates. These findings suggest a role for MAP in amyloid-induced β-cell death and a potential strategy to reduce intracellular amyloid β-cell toxicity by blocking cytochrome c apoptotic function.

Keywords: Amylin; Caspase-9; Cytochrome c; Islet amyloid; Type 2 diabetes; β-cell apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / metabolism
  • Animals
  • Apoptosis* / drug effects
  • Caspase 9 / metabolism
  • Cytochromes c / metabolism
  • Enzyme Activation / drug effects
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / pathology*
  • Islet Amyloid Polypeptide / toxicity*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Models, Biological
  • Protein Aggregates
  • Signal Transduction / drug effects
  • bcl-2-Associated X Protein / antagonists & inhibitors
  • bcl-2-Associated X Protein / metabolism

Substances

  • Islet Amyloid Polypeptide
  • Protein Aggregates
  • bcl-2-Associated X Protein
  • Cytochromes c
  • Caspase 9